Our goal is to discover drugs that will make menopausal hormone therapy (MHT) safe for long-term treatment of chronic conditions associated with menopause. Due to the increasing longevity of women, menopause has become a critical issue in Women's Health. Life expectancy for women is now 81.2 years. Unlike just a century ago, most women will reach menopause and live approximately one-third of their life after menopause. There are currently 36 million menopausal women in the U.S. and the number is projected to soar to about 50 million in 25 years. Unfortunately, menopause is associated with an increase in the incidence of osteoporosis, obesity, diabetes and metabolic syndrome. Long term exposure to MHT decreases the risk of these conditions. MHT is approved for short-term treatment of hot flashes and vaginal/vulvar symptoms, since long-term treatment with MHT is associated with an increased risk of breast cancer, cardiovascular risks and Alzheimer's disease. A major breakthrough in primary prevention for Women's Health would occur if safer MHT regimens could be developed for long-term treatment. We discovered compounds termed ER? coligands that reprogram the effects of estradiol on gene expression and cell proliferation. Our data indicate that the ER? coligand binds to the surface of ER?, at a separate binding site than estrogens, leading to an increase in binding of E2 to its binding site. The binding of both ligands simultaneously to ER? produces a change in conformation as demonstrated by an alteration in the melting temperature of ER?. These studies indicate that the conformation of the E2-ER?-ER coligand complex is distinct from the E2-ER? complex leading to the reprogramming of the E2 transcriptional and cellular effects. In fact, we found that the E2/ER? coligand combination reprograms E2 to regulate over 800 unique genes in U2OS cells. These genes are not regulated by E2 or the ER? coligand alone. It is well established that E2 stimulates the proliferation of MCF-7 breast cancer cells by binding to ER? resulting in the activation of oncogenes, such as c-MYC. We found that the ER? coligand reprograms ER? so E2 no longer causes cell proliferation, nor does it stimulate c-MYC production. The ER? coligand also blocked E2 stimulation of uterine growth in mice. Based on these findings, we hypothesize that ER? coligands can be combined with existing estrogens, used in MHT, to block the adverse proliferative action of E2 to allow the ER? coligand/estrogen combination to be used safely for long-term MHT treatment. The aim of this phase I proposal is to select a lead ER? coligand/estrogen combination that has the best safety profile in cultured cells and animals prior to advancing it to Pharmacokinetic/Pharmacodynamic and other pre-clinical testing in a phase II proposal. These studies have the potential to facilitate the early development of a new type of MHT, that can be used for long-term administration, to prevent chronic diseases associated with menopause, such as osteoporosis, obesity, diabetes and metabolic syndrome.